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Principles of Metabolic Regulation

Regulation of metabolic pathways

Metabolism is a balance of anabolic (require energy to build molecules, store energy) and catabolic (break down molecules, release energy) processes. Regulation of these processes allows an organism to meet changing demands in energy requirements both within a cell and across systems (e.g. between the liver and skeletal muscle). Regulation of metabolic pathways offers a level of control that overlays thermodynamic favorability, with spontaneous reactions controlled even in the case of no thermodynamic barrier and non-spontaneous reactions assisted in overcoming one, both dependent on enzyme catalysts to proceed.

Maintenance of a dynamic steady state

To consistently perform the work of a living organism, cells need reliable levels of metabolites (e.g amino acids) and energy sources (e.g. ATP), which can be rapidly depleted at times of high expenditure and must be replenished. Maintenance of blood glucose levels exemplifies this principle of providing a dynamic steady state, in this case with circulating glucose that can be locally oxidized for ATP production.

Regulation of glycolysis and gluconeogenesis

Glycolysis and gluconeogenesis are regulated in concert as nearly reciprocal processes: glycolysis breaksdown glucose molecules, while gluconeogenesis produces new glucose molecules from non-carbohydrate sources (compare to glycogenolysis which releases glucose molecule monomers from the polysaccharide glycogen).

Glycolysis is highly regulated by way of the enzymes that govern its three irreversible steps:

hexokinase (step 1)

phosphofructokinase (step 3)

pyruvate kinase (step 10)

The intermediate produced by step 1, glucose 6-phosphate, intersects with other pathways such as glycogenesis and the pentose phosphate pathway, thus passing the role of committed step in glycolysis to the next irreversible step, step 3. The role of step 3 as committed step gives phosphofructokinase the most control over regulation of glycolysis.

Glycolysis is inhibited when ATP is plentiful through allosteric regulation of its key enzymes. Hexokinase is regulated by the allosteric inhibition by its product glucose 6-phosphate, which backs up (increases) in the glycolysis pathway when step 3's phosphofructokinase is itself allosterically inhibited by ATP. Pyruvate kinase undergoes allosteric inhibition by ATP and by alanine derived from the product of this last step, pyruvate.

The gluconeogenesis pathway conversely is used in presence of high ATP to synthesize glucose in effort to maintain blood glucose levels. Fructose 1,6-bisphosphatase, an enzyme of gluconeogenesis, is regulated by way of activation by citrate (citric acid cycle intermediate) and inhibition by AMP (present along with low ATP levels).

Metabolism of glycogen

Glycogen is a carbohydrate storage molecule consisting of polymerized monomers of glucose. In conditions of sufficient blood glucose levels, excess glucose is stored as glycogen (or used for fatty acid synthesis). Glycogen molecules can then be broken down to release individual glucose molecules when need for glucose rises. Glycogen is mainly found in the liver, able to assist in maintenance of blood glucose levels, and in skeletal muscle for local storage.

Allosteric and hormonal control

The phosphorylation activity that regulates the opposing processes of glycogen synthesis and breakdown is in turn hormonally regulated by insulin and glucagon hormones produced in the pancreas. In high blood glucose conditions, insulin stimulates glycogen synthesis. Conversely, glucagon stimulates glycogen breakdown, working to increase blood glucose levels.

Analysis of metabolic control

Metabolic controls can be viewed as acting on one of several levels including: metabolite (substrates and products) concentrations, phosphorylation, allosteric binding on metabolic enzymes, and metabolic enzyme synthesis (transcription and translation).